title: A double-negative feedback loop between Wnt-β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma.
abstract: Wnt-β-catenin signaling participates in the epithelial-mesenchymal transition (EMT) in a variety of cancers; however, its involvement in hepatocellular carcinoma (HCC) and downstream molecular events is largely undefined. HNF4α is the most prominent and specific factor maintaining the differentiation of hepatic lineage cells and a potential EMT regulator in HCC cells. However, the molecular mechanisms by which HNF4α maintains the differentiated liver epithelium and inhibits EMT have not been completely defined. In this study, we systematically explored the relationship between Wnt-β-catenin signaling and HNF4α in the EMT process of HCC cells. Our results indicated that HNF4α expression was negatively regulated during Wnt-β-catenin signaling-induced EMT through Snail and Slug in HCC cells. In contrast, HNF4α was found to directly associate with TCF4 to compete with β-catenin but facilitate transcription co-repressor activities, thus inhibiting expression of EMT-related Wnt-β-catenin targets. Moreover, HNF4α may control the switch between the transcriptional and adhesion functions of β-catenin. Overexpression of HNF4α was found to completely compromise the Wnt-β-catenin-signaling-induced EMT phenotype. Finally, we determined the regulation pattern between Wnt-β-catenin signaling and HNF4α in rat tumor models. Our studies have identified a double-negative feedback mechanism controlling Wnt-β-catenin signaling and HNF4α expression in vitro and in vivo, which sheds new light on the regulation of EMT in HCC. The modulation of these molecular processes may be a method of inhibiting HCC invasion by blocking Wnt-β-catenin signaling or restoring HNF4α expression to prevent EMT.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology Research, School of Life Sciences, Xiamen University, Xiamen, 361102, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Li
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Anjum
authors.forename: Long-Xin
authors.initials: LX
authors.lastname: Gui
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Jia-Kun
authors.initials: JK
authors.lastname: Chen
authors.forename: Qing-Feng
authors.initials: QF
authors.lastname: Liu
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Ye
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Wang
authors.forename: Jia-Fa
authors.initials: JF
authors.lastname: Wu
authors.forename: Wang-Yu
authors.initials: WY
authors.lastname: Cai
authors.forename: Guang-Bin
authors.initials: GB
authors.lastname: Sun
authors.forename: Yun-Jia
authors.initials: YJ
authors.lastname: Liu
authors.forename: Rong-Fu
authors.initials: RF
authors.lastname: Liu
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Zhang
authors.forename: Bo-An
authors.initials: BA
authors.lastname: Li
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D000071250:Snail Family Transcription Factors; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495270:CTNNB1 protein, human; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C000604407:SNAI1 protein, human; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin
keywords: Epithelial-mesenchymal transition; HNF4α; Hepatocellular carcinoma; Wnt–β-catenin signaling